Rationally designed Rift Valley Fever Virus Vaccine

合理设计的裂谷热病毒疫苗

基本信息

批准号：
7676672
负责人：
RAMON FLICK
金额：
$ 53.57万
依托单位：
BIOPROTECTION SYSTEMS CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7676672
关键词：
Address Agriculture Andes Virus Animal Model Animals Antiviral Agents Applied Research Attenuated Attenuated Vaccines Basic Science Biochemical Biological Bioterrorism Bunyamwera virus Bunyaviridae Case Management Categories Cattle Cell Culture Techniques Cells Complementary DNA Crimean-Congo Hemorrhagic Fever Virus Culicidae Detection Development Disease Disease Outbreaks Dissection Economics Encephalitis Environmental Impact Family Future General Transcription Factors Generations Genes Genetic Transcription Genome Genus Phlebovirus Glycoproteins Goals Hantavirus Helper Viruses Hepatitis Human Immune Immune response Immune system Infection Interferons Investigation Knowledge La Crosse virus Lead Methods Molecular Mus Mutation Nairovirus National Institute of Allergy and Infectious Disease Nonstructural Protein Nucleoproteins Open Reading Frames Orthobunyavirus Pathogenicity Plasmids Play Polymerase Procedures Production Property Prophylactic treatment Recombinant Vaccines Recombinants Reporter Reporting Research Personnel Rift Valley Fever Rift Valley fever virus Role Ruminants Sheep Structural Protein System Testing Transfection Vaccine Design Vaccines Viral Viral Genes Viral Genome Viral Hemorrhagic Fevers Viral Nonstructural Proteins Viral Pathogenesis Viral Vector Virion Virulence Virulent Virus Virus Diseases Work attenuation base biodefense design experience fighting gene function genetic manipulation inhibitor/antagonist member monolayer mortality pathogen positional cloning prevent programs recombinant virus response social tool transcription factor TFIIH vaccine candidate vaccine development virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): Rift Valley fever (RVF) is a serious disease caused by a member of the Bunyaviridae family. RVFV is transmitted by mosquitoes and provokes disastrous outbreaks. Infections in humans can lead to hepatitis or encephalitis and fatal hemorrhagic fever; ruminants are also very sensitive. There is no commercial vaccine for humans and the Smithburn attenuated vaccine available for animals is teratogenic and abortogenic. Animal studies as well as biochemical analysis of infected cells have shown that the interferon response plays a critical role in attenuation but is blocked during infection with virulent strains. The nonstructural protein NSs is responsible for this blockage which occurs at the transcriptional level. To disable the innate immune evasion, NSs appears therefore as a good target. Our working hypothesis is based on the finding that interferon antagonistic action of NSs occurs via its interaction with p44 a component of the transcription factor TFIIH. Thus we propose to produce recombinant RVFV by reverse genetics in which the NSs function is abolished through NSs mutations. The proposed project is composed of three aims: i) establishment of a minigenome rescue system as a basis for the development of reverse genetics applied to RVFV, ii) production of a cDNA infectious clone system for the production of a recombinant virus and iii) production of a RVFV in which mutations in the interacting domain of NSs and p44 are introduced, the domain being determined concomitantly. The pathogenicity of this virus will be tested in the established mouse animal model to determine if the interaction of NSs with p44 is responsible for virulence. If the working hypothesis is true this virus must be avirulent. This will provide us with potential targets to develop antiviral strategies. In addition we will produce a recombinant virus which does not express any NSs protein and which must be a good vaccine candidate. In conclusion, the lack of control and prevention measures, the continued emergence of the virus in different parts of the world, and the omnipresent threat of bioterrorism make dissection of RVFV gene functions and investigation of RVFV pathogenesis a particularly urgent task. A vaccine would be extremely useful in future eradication programs by reducing infection in cattle, sheep and humans, and reducing the social, economic, and environmental impact of the disease.

描述（由申请人提供）：Rift Valley Fever（RVF）是由Bunyaviridae家族成员引起的严重疾病。 RVFV是由蚊子传播的，引起了灾难性的爆发。人类感染会导致肝炎或脑炎和致命的出血热；反刍动物也非常敏感。人类没有商业疫苗，而史密斯本可用于动物的疫苗是致死性和流产性的。动物研究以及对感染细胞的生化分析表明，干扰素反应在衰减中起关键作用，但在感染毒性菌株期间被阻塞。非结构蛋白NSS负责在转录水平上发生的这种阻塞。为了禁用先天的免疫逃避，NSS似乎是一个很好的目标。我们的工作假设是基于以下发现：干扰素通过与p44的相互作用发生转录因子TFIIH的成分发生。因此，我们建议通过反向遗传学产生重组RVFV，其中通过NSS突变消除了NSS功能。拟议的项目由三个目的组成：i）建立微型救援系统，作为开发用于RVFV的反向遗传学的基础，ii）生产cDNA感染性克隆系统，用于生产重组病毒和III）生产引入了NS和p44相互作用域中突变的RVFV，该域被同时确定。该病毒的致病性将在已建立的小鼠动物模型中进行测试，以确定NSS与p44的相互作用是否负责毒力。如果工作假设是正确的，则该病毒必须是无毒的。这将为我们提供制定抗病毒策略的潜在目标。此外，我们将产生一种重组病毒，该病毒不表达任何NSS蛋白，并且必须是良好的疫苗候选者。总之，缺乏控制和预防措施，该病毒在世界各地的持续出现以及生物恐怖主义的无所不在的威胁使RVFV基因功能的解剖和RVFV发病机理的研究是特别紧迫的任务。通过减少牛，绵羊和人类的感染并减少疾病的社会，经济和环境影响，一种疫苗在未来的根除计划中将非常有用。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Molecular biology of rift valley Fever virus.

DOI：
10.2174/1874357901004020008
发表时间：
2010-04-22
期刊：
The open virology journal
影响因子：
0
作者：
Bouloy M;Weber F
通讯作者：
Weber F

RNA polymerase I-mediated expression of viral RNA for the rescue of infectious virulent and avirulent Rift Valley fever viruses.

DOI：
10.1016/j.virol.2008.05.033
发表时间：
2008-09-01
期刊：
VIROLOGY
影响因子：
3.7
作者：
Billecocq, Agnes;Gauliard, Nicolas;Le May, Nicolas;Elliott, Richard M.;Flick, Ramon;Bouloy, Michele
通讯作者：
Bouloy, Michele

Novel suspension cell-based vaccine production systems for Rift Valley fever virus-like particles.

DOI：
10.1016/j.jviromet.2010.07.015
发表时间：
2010-11
期刊：
Journal of virological methods
影响因子：
3.1
作者：
R. Mandell;Ramesh Koukuntla;L. J. Mogler;Andrea K. Carzoli;M. Holbrook;B. K. Martin;N. Vahanian;
通讯作者：
R. Mandell;Ramesh Koukuntla;L. J. Mogler;Andrea K. Carzoli;M. Holbrook;B. K. Martin;N. Vahanian;

A replication-incompetent Rift Valley fever vaccine: chimeric virus-like particles protect mice and rats against lethal challenge.

DOI：
10.1016/j.virol.2009.11.001
发表时间：
2010-02-05
期刊：
Virology
影响因子：
3.7
作者：
Mandell RB;Koukuntla R;Mogler LJ;Carzoli AK;Freiberg AN;Holbrook MR;Martin BK;Staplin WR;Vahanian NN;Link CJ;Flick R
通讯作者：
Flick R

Reverse genetics technology for Rift Valley fever virus: current and future applications for the development of therapeutics and vaccines.